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US20090298834A1 - 4-(aminomethyl)cyclohexanamine derivatives as calcium channel blockers - Google Patents

4-(aminomethyl)cyclohexanamine derivatives as calcium channel blockers Download PDF

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Publication number
US20090298834A1
US20090298834A1 US12/420,785 US42078509A US2009298834A1 US 20090298834 A1 US20090298834 A1 US 20090298834A1 US 42078509 A US42078509 A US 42078509A US 2009298834 A1 US2009298834 A1 US 2009298834A1
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US
United States
Prior art keywords
methyl
trifluoromethyl
cyclohexyl
alkyl
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/420,785
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English (en)
Inventor
Hassan Pajouhesh
Ramesh KAUL
Mike GRIMWOOD
Jason Tan
Yuanxi Zhou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Taro Pharmaceuticals Inc
Original Assignee
Neuromed Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neuromed Pharmaceuticals Ltd filed Critical Neuromed Pharmaceuticals Ltd
Priority to US12/420,785 priority Critical patent/US20090298834A1/en
Priority to CA2722723A priority patent/CA2722723A1/fr
Priority to PCT/CA2009/000767 priority patent/WO2009146539A1/fr
Assigned to NEUROMED PHARMACEUTICALS LTD. reassignment NEUROMED PHARMACEUTICALS LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: TAN, JASON, ZHOU, YUANXI, KAUL, RAMESH, GRIMWOOD, MIKE, PAJOUHESH, HASSAN
Publication of US20090298834A1 publication Critical patent/US20090298834A1/en
Assigned to ZALICUS PHARMACEUTICALS LTD. reassignment ZALICUS PHARMACEUTICALS LTD. CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: NEUROMED PHARMACEUTICALS LTD.
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/28—Nitrogen atoms
    • C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to compounds useful in treating conditions associated with calcium channel function, and particularly conditions associated with T-type calcium channel activity. More specifically, the invention concerns compounds containing substituted 4-(aminomethyl)cyclohexanamine derivatives that are useful in treatment of conditions such as cardiovascular disease, epilepsy and pain.
  • calcium channels directly affect membrane potential and contribute to electrical properties such as excitability, repetitive firing patterns and pacemaker activity. Calcium entry further affects neuronal functions by directly regulating calcium-dependent ion channels and modulating the activity of calcium-dependent enzymes such as protein kinase C and calmodulin-dependent protein kinase II.
  • An increase in calcium concentration at the presynaptic nerve terminal triggers the release of neurotransmitter, which also affects neurite outgrowth and growth cone migration in developing neurons.
  • Examples of calcium-mediated human disorders include but are not limited to congenital migraine, cerebellar ataxia, angina, epilepsy, hypertension, ischemia, and some arrhythmias.
  • the clinical treatment of some of these disorders has been aided by the development of therapeutic calcium channel antagonists (e.g., dihydropyridines, phenylalkyl amines, and benzothiazapines all target L-type calcium channels) (Janis, R. J. & Triggle, D. J., In Calcium Channels: Their Properties, Functions, Regulation nad Clinical Relevance (1991) CRC Press, London).
  • T-type (or low voltage-activated) channels describe a broad class of molecules that transiently activate at negative potentials and are highly sensitive to changes in resting potential.
  • T-type channels activate at more positive potentials (high voltage-activated) and display diverse kinetics and voltage-dependent properties (Catterall (2000); Huguenard (1996)).
  • T-type channels can be distinguished by having a more negative range of activation and inactivation, rapid inactivation, slow deactivation, and smaller single-channel conductances.
  • T-type calcium channels are involved in various medical conditions. In mice lacking the gene expressing the ⁇ 1G subunit, resistance to absence seizures was observed (Kim, C. et al., Mol Cell Neurosci (2001) 18(2): 235-245). Other studies have also implicated the ⁇ 1H subunit in the development of epilepsy (Su, H. et al., J Neurosci (2002) 22: 3645-3655). There is strong evidence that some existing anticonvulsant drugs, such as ethosuximide, function through the blockade of T-type channels (Gomora, J. C., et al., Mol Pharmacol (2001) 60: 1121-1132).
  • Low voltage-activated calcium channels are highly expressed in tissues of the cardiovascular system.
  • Mibefradil a calcium channel blocker 10-30 fold selective for T-type over L-type channels, was approved for use in hypertension and angina. It was withdrawn from the market shortly after launch due to interactions with other drugs (Heady, T. N., et al., Jpn J Pharmacol. (2001) 85:339-350).
  • T-type calcium channels are also involved in pain (see for example: US Patent Application No. 2003/086980; PCT Patent Application Nos. WO 03/007953 and WO 04/000311). Both mibefradil and ethosuximide have shown anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain in rats (Dogrul, A., et al., Pain (2003) 105:159-168). In addition to cardiovascular disease, epilepsy (see also US Patent Application No. 2006/025397), and chronic and acute pain, T-type calcium channels have been implicated in diabetes (US Patent Application No. 2003/125269), certain types of cancer such as prostate cancer (PCT Patent Application Nos.
  • WO 05/086971 and WO 05/77082 sleep disorders (US Patent Application No. 2006/003985), Parkinson's disease (US Patent Application No. 2003/087799); psychosis such as schizophrenia (US Patent Application No. 2003/087799), overactive bladder (Sui, G.-P., et al., British Journal of Urology International (2007) 99(2): 436-441; see also US 2004/197825), renal disease (Hayashi, K., et al., Journal of Pharmacological Sciences (2005) 99: 221-227), neuroprotection and male birth control.
  • the invention relates to compounds useful in treating conditions modulated by calcium channel activity and in particular conditions mediated by T-type channel activity.
  • the compounds of the invention are N-piperidinyl acetamide derivatives with structural features that enhance the calcium channel blocking activity of the compounds.
  • the invention is directed to a method of treating conditions mediated by calcium channel activity by administering to patients in need of such treatment at least one compound of formula (1):
  • A is C(O)NH or NHC(O);
  • X is an optionally substituted alkylene (1-4C), heteroalkylene (2-4C), alkenylene (2-4C), or heteroakenylene (2-4C);
  • n and p are independently 0 or 1;
  • Ar is an optionally substituted aryl (6-10C) or heteroaryl (5-12 ring members);
  • each Y is independently H, SR′, SOR′, SO 2 R′, wherein each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6), heteroalkynyl (2-6C); or each Y is an optionally substituted group selected from alkyl (1-10C), alkenyl (2-10C), alkynyl (2-10C), heteroalkyl (2-10C), heteroalkenyl (2-10C), heteroalkynyl (2-10C), aryl (6-12C)-alkyl (1-6C) or heteroaryl (5-12 ring members)-alkyl (1-6C); or two Y may together form an optionally substituted heterocyclic ring (4-6 ring members);
  • each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6), heteroalkynyl (2-6C); or each substituent is alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C); aryl (6-10C), heteroary
  • the invention is also directed to the use of compounds of formula (1) for the preparation of medicaments for the treatment of conditions requiring modulation of calcium channel activity, and in particular T-type calcium channel activity.
  • the invention is directed to pharmaceutical compositions containing compounds of formula (1) in admixture with a pharmaceutically acceptable excipient with the additional provisos that Ar is not a naphthyl and that the two Y do not together form a pyrrolidin-2-onyl ring.
  • the invention is directed to the use of these compositions for treating conditions requiring modulation of calcium channel activity, and particularly T-type calcium channel activity.
  • the invention is also directed to compounds of formula (1) useful to modulate calcium channel activity, particularly T-type channel activity.
  • alkyl As used herein, the term “alkyl,” “alkenyl” and “alkynyl” include straight-chain, branched-chain and cyclic monovalent substituents, as well as combinations of these, containing only C and H when unsubstituted. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butynyl, and the like. Typically, the alkyl, alkenyl and alkynyl groups contain 1-10C (alkyl) or 2-10C (alkenyl or alkynyl).
  • they contain 1-8C, 1-6C, 1-4C, 1-3C or 1-2C (alkyl); or 2-8C, 2-6C, 2-4C or 2-3C (alkenyl or alkynyl).
  • any hydrogen atom on one of these groups can be replaced with a halogen atom, and in particular a fluoro or chloro, and still be within the scope of the definition of alkyl, alkenyl and alkynyl.
  • CF 3 is a 1C alkyl.
  • Heteroalkyl, heteroalkenyl and heteroalkynyl are similarly defined and contain at least one carbon atom but also contain one or more O, S or N heteroatoms or combinations thereof within the backbone residue whereby each heteroatom in the heteroalkyl, heteroalkenyl or heteroalkynyl group replaces one carbon atom of the alkyl, alkenyl or alkynyl group to which the heteroform corresponds.
  • the heteroalkyl, heteroalkenyl and heteroalkynyl groups have C at each terminus to which the group is attached to other groups, and the heteroatom(s) present are not located at a terminal position. As is understood in the art, these heteroforms do not contain more than three contiguous heteroatoms.
  • the heteroatom is O or N.
  • heteroalkyl is defined as 1-6C, it will contain 1-6 C, N, O, or S atoms such that the heteroalkyl contains at least one C atom and at least one heteroatom, for example 1-5C and 1N or 1-4C and 2N.
  • heteroalkyl is defined as 1-6C or 1-4C, it would contain 1-5C or 1-3C respectively, i.e., at least one C is replaced by O, N or S.
  • heteroalkenyl or heteroalkynyl when defined as 2-6C (or 2-4C), it would contain 2-6 or 2-4 C, N, O, or S atoms, since the heteroalkenyl or heteroalkynyl contains at least one carbon atom and at least one heteroatom, e.g. 2-5C and 1N or 2-4C and 2O. Further, heteroalkyl, heteroalkenyl or heteroalkynyl substituents may also contain one or more carbonyl groups.
  • heteroalkyl, heteroalkenyl and heteroalkynyl groups include CH 2 OCH 3 , CH 2 N(CH 3 ) 2 , CH 2 OH, (CH 2 ) n NR 2 , OR, COOR, CONR 2 , (CH 2 ) n OR, (CH 2 ) n COR, (CH 2 ) n COOR, (CH 2 ) n SR, (CH 2 ) n SOR, (CH 2 ) n SO 2 R, (CH 2 ) n CONR 2 , NRCOR, NRCOOR, OCONR 2 , OCOR and the like wherein the group contains at least one C and the size of the substituent is consistent with the definition of alkyl, alkenyl and alkynyl.
  • “Aromatic” moiety or “aryl” moiety refers to any monocyclic or fused ring bicyclic system which has the characteristics of aromaticity in terms of electron distribution throughout the ring system and includes a monocyclic or fused bicyclic moiety such as phenyl or naphthyl; “heteroaromatic” or “heteroaryl” also refers to such monocyclic or fused bicyclic ring systems containing one or more heteroatoms selected from O, S and N. The inclusion of a heteroatom permits inclusion of 5-membered rings to be considered aromatic as well as 6-membered rings.
  • typical aromatic/heteroaromatic systems include pyridyl, pyrimidyl, indolyl, benzimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, benzoisoxazolyl, imidazolyl and the like. Because tautomers are theoretically possible, phthalimido is also considered aromatic.
  • the ring systems contain 5-12 ring member atoms or 6-10 ring member atoms.
  • the aromatic or heteroaromatic moiety is a 6-membered aromatic rings system optionally containing 1-2 nitrogen atoms. More particularly, the moiety is an optionally substituted phenyl, pyridyl, indolyl, pyrimidyl, pyridazinyl, benzothiazolyl or benzimidazolyl, pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, benzothiazolyl, indolyl. Even more particularly, such moiety is phenyl, pyridyl, or pyrimidyl and even more particularly, it is phenyl.
  • O-aryl or “O-heteroaryl” refers to aromatic or heteroaromatic systems which are coupled to another residue through an oxygen atom.
  • a typical example of an O-aryl is phenoxy.
  • arylalkyl refers to aromatic and heteroaromatic systems which are coupled to another residue through a carbon chain, saturated or unsaturated, typically of 1-8C, 1-6C or more particularly 1-4C or 1-3C when saturated or 2-8C, 2-6C, 2-4C or 2-3C when unsaturated, including the heteroforms thereof.
  • arylalkyl thus includes an aryl or heteroaryl group as defined above connected to an alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl or heteroalkynyl moiety also as defined above.
  • Typical arylalkyls would be an aryl(6-12C)alkyl(1-8C), aryl(6-12C)alkenyl(2-8C), or aryl(6-12C)alkynyl(2-8C), plus the heteroforms.
  • a typical example is phenylmethyl, commonly referred to as benzyl.
  • Typical optional substituents on aromatic or heteroaromatic groups include independently halo, CN, NO 2 , CF 3 , OCF 3 , COOR′, CONR′ 2 , OR′, SR′, SOR′, SO 2 R′, NR′ 2 , NR′(CO)R′, NR′C(O)OR′, NR′C(O)NR′ 2 , NR′SO 2 NR′ 2 , or NR′SO 2 R′, wherein each R′ is independently H or an optionally substituted group selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and aryl (all as defined above); or the substituent may be an optionally substituted group selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, O-aryl, O-heteroaryl and ary
  • Optional substituents on a non-aromatic group are typically selected from the same list of substituents suitable for aromatic or heteroaromatic groups and may further be selected from ⁇ O and ⁇ NOR′ where R′ is H or an optionally substituted group selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and aryl (all as defined above).
  • Halo may be any halogen atom, especially F, Cl, Br, or I, and more particularly it is fluoro, chloro or bromo and even more particularly it is fluoro or chloro.
  • any alkyl, alkenyl, alkynyl, or aryl (including all heteroforms defined above) group contained in a substituent may itself optionally be substituted by additional substituents.
  • the nature of these substituents is similar to those recited with regard to the substituents on the basic structures above.
  • this alkyl may optionally be substituted by the remaining substituents listed as substituents where this makes chemical sense, and where this does not undermine the size limit of alkyl per se; e.g., alkyl substituted by alkyl or by alkenyl would simply extend the upper limit of carbon atoms for these embodiments, and is not included.
  • alkyl substituted by aryl, amino, halo and the like would be included.
  • A is C(O)NH or NHC(O).
  • “p” is 0 or 1 indicating that X is present when n is 1 and X is absent when p is 0.
  • X is an optionally substituted alkylene (1-4C), heteroalkylene (2-4C), alkenylene (2-4C), or heteralkenylene (2-4C).
  • X is methylene.
  • the optional substituents on X are as defined above, however, in particular embodiments X may be unsubstituted.
  • m and n may each be 0 or 1. In more particular embodiments, at least one of m and n must be 1. In concurrent or alternate embodiments, A is NHC(O) if n is 0.
  • Ar is an optionally substituted aryl (6-10C) or heteroaryl (5-12 ring members).
  • Ar is an optionally substituted phenyl, oxadiazolyl, thiazolyl, pyridinyl, or isoxazolyl.
  • Ar is an optionally substituted phenyl.
  • Optional substituents on Ar are as defined above, however, in more particular embodiments such optional substituents may independently be selected from fluoro, chloro, trifluoromethyl, methyl, ethyl, trifluoromethoxy, t-butyl, t-butyloxy, methoxy, phenyl, or tolyl.
  • Each Y is independently H, SR′, SOR′, SO 2 R′, wherein each R′ is independently H or an optionally substituted group selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl; or each Y is an optionally substituted group selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteralkynyl, aryl-alkyl, heteroaryl-alkyl; or two Y may together form an optionally substituted heterocyclic ring.
  • at least one Y is a hydrogen whereas in other embodiments both Y are hydrogen.
  • At least one Y is an alkyl, heteroalkyl, arylalkyl or heteroarylalkyl.
  • a carbonyl in Y is adjacent to the N.
  • two Y together form an optionally substituted heterocyclic ring, such as a pyrrolidinyl, piperidinyl, oxazolidinyl, morpholino.
  • the two Y groups together form an optionally substituted 2-oxooxazolidinyl.
  • the compound of the invention is of formula (2) as follows:
  • Y is as defined above and each R is independently H, fluoro, chloro, trifluoromethyl, methyl, ethyl, trifluoromethoxy, t-butyl, t-butyloxy or methoxy.
  • two or more of the particularly described groups are combined into one compound: it is often suitable to combine one of the specified embodiments of one feature as described above with a specified embodiment or embodiments of one or more other features as described above.
  • a specified embodiment includes a compound of formula (1) with Ar equal to phenyl, and another specified embodiment has n equal to 1.
  • one Y is H and in others A is NHC(O).
  • additional preferred embodiments include Y as H in combination with any of the preferred combinations set forth above; other preferred combinations include A as NHC(O) in combination with any of the preferred combinations set forth above.
  • the compounds of the invention may be in the form of pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well-known in the art, such as hydrochloric, sulphuric, hydrobromic, acetic, lactic, citric, or tartaric acids for forming acid addition salts, and potassium hydroxide, sodium hydroxide, ammonium hydroxide, caffeine, various amines, and the like for forming basic salts. Methods for preparation of the appropriate salts are well-established in the art.
  • the compounds of the invention contain one or more chiral centers.
  • the invention includes each of the isolated stereoisomeric forms as well as mixtures of stereoisomers in varying degrees of chiral purity, including racemic mixtures. It also encompasses the various diastereomers and tautomers that can be formed.
  • Compounds of formula (1) are also useful for the manufacture of a medicament useful to treat conditions characterized by undesired T-type calcium channel activities.
  • the compounds of the invention may be coupled through conjugation to substances designed to alter the pharmacokinetics, for targeting, or for other reasons.
  • the invention further includes conjugates of these compounds.
  • polyethylene glycol is often coupled to substances to enhance half-life; the compounds may be coupled to liposomes covalently or noncovalently or to other particulate carriers. They may also be coupled to targeting agents such as antibodies or peptidomimetics, often through linker moieties.
  • the invention is also directed to the compounds of formula (1) when modified so as to be included in a conjugate of this type.
  • the compounds of formula (1) are useful in the methods of the invention and, while not bound by theory, are believed to exert their desirable effects through their ability to modulate the activity of calcium channels, particularly the activity of T-type calcium channels. This makes them useful for treatment of certain conditions where modulation of T-type calcium channels is desired, including: cardiovascular disease; epilepsy; diabetes; cancer; pain, including both chronic and acute pain; sleep disorders; Parkinson's disease; psychosis such as schizophrenia; overactive bladder; renal disease, neuroprotection, addiction and male birth control.
  • Cardiovascular disease as used herein includes but is not limited to hypertension, pulmonary hypertension, arrhythmia (such as atrial fibrillation and ventricular fibrillation), congestive heart failure, and angina pectoris.
  • Epilepsy as used herein includes but is not limited to partial seizures such as temporal lobe epilepsy, absence seizures, generalized seizures, and tonic/clonic seizures.
  • Cancer as used herein includes but is not limited to breast carcinoma, neuroblastoma, retinoblastoma, glioma, prostate carcinoma, esophageal carcinoma, fibrosarcoma, colorectal carcinoma, pheochromocytoma, adrenocarcinoma, insulinoma, lung carcinoma, melanoma, and ovarian cancer.
  • Acute pain as used herein includes but is not limited to nociceptive pain and post-operative pain.
  • Chronic pain includes but is not limited by: peripheral neuropathic pain such as post-herpetic neuralgia, diabetic neuropathic pain, neuropathic cancer pain, failed back-surgery syndrome, trigeminal neuralgia, and phantom limb pain; central neuropathic pain such as multiple sclerosis related pain, Parkinson disease related pain, post-stroke pain, post-traumatic spinal cord injury pain, and pain in dementia; musculoskeletal pain such as osteoarthritic pain and fibromyalgia syndrome; inflammatory pain such as rheumatoid arthritis and endometriosis; headache such as migraine, cluster headache, tension headache syndrome, facial pain, headache caused by other diseases; visceral pain such as interstitial cystitis, irritable bowel syndrome and chronic pelvic pain syndrome; and mixed pain such as lower back pain, neck and shoulder pain, burning mouth syndrome and complex regional pain syndrome.
  • use of compounds of the present invention to treat osteoarthritic pain inherently includes use of such compounds to improve joint mobility in patients suffering from osteoarthritis.
  • Addiction includes but is not limited to dependence, withdrawal and/or relapse of cocaine, opioid, alcohol and nicotine
  • T-type channels in conditions associated with neural transmission would indicate that compounds of the invention which target T-type receptors are most useful in these conditions.
  • Many of the members of the genus of compounds of formula (1) exhibit high affinity for T-type channels. Thus, as described below, they are screened for their ability to interact with T-type channels as an initial indication of desirable function. It is particularly desirable that the compounds exhibit IC 50 values of ⁇ 1 ⁇ M.
  • the IC 50 is the concentration which inhibits 50% of the calcium, barium or other permeant divalent cation flux at a particular applied potential.
  • the compound has very low activity with respect to the hERG K + channel which is expressed in the heart. Compounds that block this channel with high potency may cause reactions which are fatal. Thus, for a compound that modulates the calcium channel, it is preferred that the hERG K + channel is not inhibited. Some inhibition of the hERG K + channel may be tolerated in a drug as long as the compound is sufficiently selective for the target of interest over the hERG K + channel. For example, 10 fold selectivity of a T-type calcium channel over the hERG K + channel would be beneficial and more preferably 30 fold selectivity or 100 fold selectivity.
  • the compound will be evaluated for calcium ion channel type specificity by comparing its activity among the various types of calcium channels, and specificity for one particular channel type is preferred. The compounds which progress through these tests successfully are then examined in animal models as actual drug candidates.
  • the compounds of the invention modulate the activity of calcium channels; in general, said modulation is the inhibition of the ability of the channel to transport calcium.
  • modulation is the inhibition of the ability of the channel to transport calcium.
  • the effect of a particular compound on calcium channel activity can readily be ascertained in a routine assay whereby the conditions are arranged so that the channel is activated, and the effect of the compound on this activation (either positive or negative) is assessed. Typical assays are described hereinbelow in Example 15.
  • the compounds of the invention can be synthesized individually using methods known in the art per se, or as members of a combinatorial library.
  • the libraries contain compounds with various substituents and various degrees of unsaturation, as well as different chain lengths.
  • the libraries which contain, as few as 10, but typically several hundred members to several thousand members, may then be screened for compounds which are particularly effective against a specific subtype of calcium channel, e.g., the N-type channel.
  • the libraries may be screened for compounds that block additional channels or receptors such as sodium channels, potassium channels and the like.
  • Methods of performing these screening functions are well known in the art. These methods can also be used for individually ascertaining the ability of a compound to agonize or antagonize the channel.
  • the channel to be targeted is expressed at the surface of a recombinant host cell such as human embryonic kidney cells.
  • the ability of the members of the library to bind the channel to be tested is measured, for example, by the ability of the compound in the library to displace a labeled binding ligand such as the ligand normally associated with the channel or an antibody to the channel. More typically, ability to antagonize the channel is measured in the presence of calcium, barium or other permeant divalent cation and the ability of the compound to interfere with the signal generated is measured using standard techniques.
  • one method involves the binding of radiolabeled agents that interact with the calcium channel and subsequent analysis of equilibrium binding measurements including, but not limited to, on rates, off rates, K d values and competitive binding by other molecules.
  • Another method involves the screening for the effects of compounds by electrophysiological assay whereby individual cells are impaled with a microelectrode and currents through the calcium channel are recorded before and after application of the compound of interest.
  • Another method, high-throughput spectrophotometric assay utilizes loading of the cell lines with a fluorescent dye sensitive to intracellular calcium concentration and subsequent examination of the effects of compounds on the ability of depolarization by potassium chloride or other means to alter intracellular calcium levels.
  • open-channel blockers are assessed by measuring the level of peak current when depolarization is imposed on a background resting potential of about ⁇ 100 mV in the presence and absence of the candidate compound. Successful open-channel blockers will reduce the peak current observed and may accelerate the decay of this current.
  • Compounds that are inactivated channel blockers are generally determined by their ability to shift the voltage dependence of inactivation towards more negative potentials.
  • a library of compounds of formula (1) can be used to identify a compound having a desired combination of activities that includes activity against at least one type of calcium channel.
  • the library can be used to identify a compound having a suitable level of activity on T-type calcium channels while having minimal activity on HERG K+channels.
  • the compounds of the invention can be formulated as pharmaceutical or veterinary compositions.
  • a summary of such techniques is found in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton, Pa., incorporated herein by reference.
  • the compounds of formula (1) may be used alone, as mixtures of two or more compounds of formula (1) or in combination with other pharmaceuticals.
  • An example of other potential pharmaceuticals to combine with the compounds of formula (1) would include pharmaceuticals for the treatment of the same indication but having a different mechanism of action from T-type calcium channel blocking.
  • a compound of formula (1) may be combined with another pain relief treatment such as an NSAID, or a compound which selectively inhibits COX-2, or an opioid, or an adjuvant analgesic such as an antidepressant.
  • Another example of a potential pharmaceutical to combine with the compounds of formula (1) would include pharmaceuticals for the treatment of different yet associated or related symptoms or indications.
  • the compounds will be formulated into suitable compositions to permit facile delivery.
  • the compounds of the invention may be prepared and used as pharmaceutical compositions comprising an effective amount of at least one compound of formula (1) admixed with a pharmaceutically acceptable carrier or excipient, as is well known in the art.
  • Formulations may be prepared in a manner suitable for systemic administration or topical or local administration.
  • Systemic formulations include those designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration.
  • the formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, preservatives and the like.
  • the compounds can be administered also in liposomal compositions or as microemulsions.
  • formulations can be prepared in conventional forms as liquid solutions or suspensions or as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions.
  • Suitable excipients include, for example, water, saline, dextrose, glycerol and the like.
  • Such compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as, for example, sodium acetate, sorbitan monolaurate, and so forth.
  • Systemic administration may also include relatively noninvasive methods such as the use of suppositories, transdermal patches, transmucosal delivery and intranasal administration.
  • Oral administration is also suitable for compounds of the invention. Suitable forms include syrups, capsules, tablets, as is understood in the art.
  • the dosage of the compounds of the invention is typically 0.01-15 mg/kg, preferably 0.1-10 mg/kg.
  • dosage levels are highly dependent on the nature of the condition, drug efficacy, the condition of the patient, the judgment of the practitioner, and the frequency and mode of administration. Optimization of the dosage for a particular subject is within the ordinary level of skill in the art.
  • reaction mixture was then diluted with CH 2 Cl 2 (50 mL), washed with 0.1N aqueous HCl (2 ⁇ 150 mL) and saturated aqueous NaHCO 3 (150 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated at 0° C. to 25 mL. 1 mL of this stock solution ( ⁇ 0.6 mmol) was then added to pre-dissolved N-((trans-4-aminocyclohexyl)methyl)-3,5-bis(trifluoromethyl)benzamide (0.2 g, 0.55 mmol) in 3 mL of CH 2 Cl 2 . The mixture was stirred at RT for 3 h.
  • T-type calcium channel blocking activity was assayed in human embryonic kidney cells, HEK 293, stably transfected with the T-type calcium channel subunits. Briefly, cells were cultured in Dulbecco's modified eagle medium (DMEM) supplemented with 10% fetal bovine serum, 200 U/ml penicillin and 0.2 mg/ml streptomycin at 37° C. with 5% CO 2 . At 85% confluency cells were split with 0.25% trypsin/1 mM EDTA and plated at 10% confluency on glass coverslips. At 12 hours the medium was replaced and the cells stably transfected using a standard calcium phosphate protocol and the appropriate calcium channel cDNA's. Fresh DMEM was supplied and the cells transferred to 28° C./5% CO 2 . Cells were incubated for 1 to 2 days prior to whole cell recording.
  • DMEM Dulbecco's modified eagle medium
  • Standard patch-clamp techniques were employed to identify blockers of T-type currents. Briefly, previously described HEK cell lines stably expressing human ⁇ 1G , ⁇ 1H and ⁇ 1I T-type channels were used for all the recordings (passage #: 4-20, 37° C., 5% CO 2 ). Whole cell patch clamp experiments were performed using an Axopatch 200B amplifier (Axon Instruments, Burlingame, Calif.) linked to a personal computer equipped with pCLAMP software. Data were analyzed using Clampfit (Axon Instruments) and SigmaPlot 4.0 (Jandel Scientific).
  • the holding potential is set at ⁇ 110 mV and with a pre-pulse at ⁇ 100 mV for 1 second prior to the test pulse at ⁇ 40 mV for 50 ms.
  • the pre-pulse is at approximately ⁇ 85 mV for 1 second, which inactivates about 15% of the T-type channels.
  • Test compounds were dissolved in external solution, 0.1-0.01% DMSO. After 10 min rest, they were applied by gravity close to the cell using a WPI microfil tubing. The “non-inactivated” pre-pulse was used to examine the resting block of a compound. The “inactivated” protocol was employed to study voltage-dependent block. However, the initial data shown below were mainly obtained using the non-inactivated protocol only. .
  • IC 50 values are shown for various compounds of the invention in Table 4 for the drug of interest. Values are shown in ⁇ M and values above 10 ⁇ M are simply represented as 10 ⁇ M. Similarly, IC 50 values for ⁇ 1G below 0.30 ⁇ M are simply represented as 0.30 ⁇ M.
  • the Spinal Nerve Ligation is an animal model representing peripheral nerve injury generating a neuropathic pain syndrome. In this model experimental animals develop the clinical symptoms of tactile allodynia and hyperalgesia. L5/L6 Spinal nerve ligation (SNL) injury was induced using the procedure of Kim and Chung (Kim, S. H., et al., Pain (1992) 50:355-363) in male Sprague-Dawley rats (Harlan; Indianapolis, Ind.) weighing 200 to 250 grams.
  • a home-made glass Chung rod was used to hook L5 or L6 and a pre-made slip knot of 4.0 silk suture was placed on the tip of the rod just above the nerve and pulled underneath to allow for the tight ligation.
  • the L5 and L6 spinal nerves were tightly ligated distal to the dorsal root ganglion. The incision was closed, and the animals were allowed to recover for 5 days. Rats that exhibited motor deficiency (such as paw-dragging) or failure to exhibit subsequent tactile allodynia were excluded from further testing.
  • Sham control rats underwent the same operation and handling as the experimental animals, but without SNL.
  • baseline behavioural testing data Prior to initiating drug delivery, baseline behavioural testing data is obtained. At selected times after infusion of the Test or Control Article behavioural data can then be collected again.
  • the assessment of tactile allodynia consisted of measuring the withdrawal threshold of the paw ipsilateral to the site of nerve injury in response to probing with a series of calibrated von Frey filaments (innocuous stimuli). Animals were acclimated to the suspended wire-mesh cages for 30 min before testing. Each von Frey filament was applied perpendicularly to the plantar surface of the ligated paw of rats for 5 sec. A positive response was indicated by a sharp withdrawal of the paw. For rats, the first testing filament is 4.31. Measurements were taken before and after administration of test articles. The paw withdrawal threshold was determined by the non-parametric method of Dixon (Dixon, W., Ann. Rev. Pharmacol. Toxicol.
  • the cut-off values for rats were no less than 0.2 g and no higher than 15 g (5.18 filament); for mice no less than 0.03 g and no higher than 2.34 g (4.56 filament).
  • a significant drop of the paw withdrawal threshold compared to the pre-treatment baseline is considered tactile allodynia.
  • FIG. 1 is a plot of the antiallodynic effects of compounds 1, 9 and vehicle (i.p.) tested in SNL L5/L6 rats using von Frey at 60 minutes compared to baseline and post-SNL.
  • Hargreaves and colleagues can be employed to assess paw-withdrawal latency to a noxious thermal stimulus.
  • Rats were allowed to acclimate within a Plexiglas enclosure on a clear glass plate for 30 minutes.
  • a radiant heat source i.e., halogen bulb coupled to an infrared filter
  • Paw-withdrawal latency can be determined by a photocell that halted both lamp and timer when the paw is withdrawn.
  • the latency to withdrawal of the paw from the radiant heat source was determined prior to L5/L6 SNL, 7-14 days after L5/L6 SNL but before drug, as well as after drug administration.
  • a maximal cut-off of 33 seconds is employed to prevent tissue damage. Paw withdrawal latency can be thus determined to the nearest 0.1 second.
  • a significant drop of the paw withdrawal latency from the baseline indicates the status of thermal hyperalgesia.
  • Antinociception is indicated by a reversal of thermal hyperalgesia to the pre-treatment baseline or a significant (p ⁇ 0.05) increase in paw withdrawal latency above this baseline.
  • Data is converted to % anti hyperalgesia or % anti nociception by the formula: (100 ⁇ (test latency ⁇ baseline latency)/(cut-off ⁇ baseline latency) where cut-off is 21 seconds for determining anti hyperalgesia and 40 seconds for determining anti nociception.
  • FIG. 2 is a plot of the anti-hyperalgesic effects of compounds 1, 9 and vehicle (i.p.) tested in SNL L5/L6 rats using radiant heat at 60 minutes compared to baseline and post-SNL.
  • ECS Electroconvulsive Shock
  • the proconvulsant or anticonvulsant activity of compounds can be evaluated using the electroconvulsive shock threshold test following the method described by Swinyard et al., (J. Pharmacol. Exp. Ther., 106, 319-330, 1952).
  • a rectangular electroconvulsive shock is administered to OF1 mice for 0.4 s at 50 Hz, via corneal electrodes connected to a constant current shock generator (Ugo Basile: Type 7801).
  • the threshold for tonic convulsions is determined as follows: The first animal is exposed to 30 mA. If the first animal does not exhibit tonic convulsions within 5 seconds, the second animal is exposed to 40 mA, and so on (increments of 10 mA) until the first tonic convulsion is observed. Once the first tonic convulsion is observed, the intensity of ECS is decreased by 5 mA for the next animal and then the intensity is decreased or increased by 5 mA from animal to animal depending on whether the previous animal convulsed or not. The minimum intensity given is 5 mA and the maximum intensity given is 95 mA.
  • Each treatment group consists of a number mice that are all exposed to ECS, but only the first 3 animals are used to estimate the threshold current and are not included in the analysis.
  • each test substance is evaluated at multiple doses, administered i.p. or p.o., prior to ECS to coincide with times of peak optimal effect (Tmax), and compared with a vehicle control group.
  • Diazepam administered under the same experimental conditions can be used as reference substance and the vehicle alone can be administered as a vehicle control.
  • results are reported as the mean intensity administered, number of deaths and percent change from control for each treatment group for approximately 30 minutes after the animal receives the ECS.
  • a positive percent change indicates an anticonvulsant effect whereas a negative percent change indicates a proconvulsant effect.
  • data intensity
  • the effects of the reference substance can be analyzed using a Student's t test.

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Cited By (11)

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US20090298883A1 (en) * 2008-06-02 2009-12-03 Hassan Pajouhesh N-piperidinyl acetamide derivatives as calcium channel blockers
US20090312346A1 (en) * 2006-05-11 2009-12-17 Neuromed Pharmaceuticals Ltd. Method for increasing the bioavailability of benzhydryl piperazine containing compounds
US20100035898A1 (en) * 2008-08-07 2010-02-11 David Beattie Organic compounds
US20120220564A1 (en) * 2009-09-18 2012-08-30 Zalicus Pharmaceuticals Ltd. Selective calcium channel modulators
US8409560B2 (en) 2011-03-08 2013-04-02 Zalicus Pharmaceuticals Ltd. Solid dispersion formulations and methods of use thereof
US8591944B2 (en) 2011-03-08 2013-11-26 Zalicus Pharmaceuticals Ltd. Solid dispersion formulations and methods of use thereof
US9340549B2 (en) 2012-03-05 2016-05-17 Amgen Inc. Oxazolidinone compounds and derivatives thereof
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US8822463B2 (en) * 2010-09-29 2014-09-02 Sk Biopharmaceuticals Co., Ltd. Methylcyclohexane derivatives and uses thereof
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WO2023192665A2 (fr) * 2022-04-01 2023-10-05 Praxis Precision Medicines, Inc. Modulateurs des canaux calciques de type t et leurs procédés d'utilisation

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5989920A (en) * 1994-12-02 1999-11-23 Synaptic Pharmaceutical Corporation Methods of modifying feeding behavior compounds useful in such methods and DNA encoding a hypothalmic atypical neuropeptide Y/peptide YY receptor Y5
US20030087799A1 (en) * 2001-11-07 2003-05-08 Jakob Wolfart Modulation
US20030086980A1 (en) * 2001-11-02 2003-05-08 Hee-Sup Shin Method for the suppression of visceral pain by regulating T type calcium channel
US20030125269A1 (en) * 1998-08-26 2003-07-03 Ming Li T-type calcium channel
US20040197825A1 (en) * 2003-01-15 2004-10-07 Millennium Pharmaceuticals, Inc. Methods and compositions for treating urological disorders using 44390, 54181, 211, 5687, 884, 1405, 636, 4421, 5410, 30905, 2045, 16405, 18560, 2047, 33751, 52872, 14063, 20739, 32544, 43239, 44373, 51164, 53010, 16852, 1587, 2207, 22245, 2387, 52908, 69112, 14990, 18547, 115, 579, 15985, 15625, 760, 18603, 2395, 2554, 8675, 32720, 4809, 14303, 16816, 17827, 32620, 577, 619, 1423, 2158, 8263, 15402, 16209, 16386, 21165, 30911, 41897, 1643, 2543, 9626, 13231, 32409, 84260, 2882, 8203, 32678, or 55053
US20060003985A1 (en) * 2002-10-17 2006-01-05 Renger John J Enhancement of sleep with t-type calcium channel antagonists
US20060025397A1 (en) * 2001-10-26 2006-02-02 Hee-Sup Shin Method of resistance of epilepsy by suppressing the function of alpha 1g protein
US20070010671A1 (en) * 2003-03-31 2007-01-11 Yoshinori Sekiguchi Novel quinazoline derivatives and methods of treatment related to the use thereof
US20070037836A1 (en) * 2001-10-01 2007-02-15 Yoshinori Sekiguchi Mch receptor antagonists
US20070129347A1 (en) * 2004-05-10 2007-06-07 Gruenenthal Gmbh Cyclohexylacetic acid compounds
US20080090863A1 (en) * 2004-09-30 2008-04-17 Taisho Pharmaceutical Co., Ltd. Pyridine Derivatives and Their Use as Medicaments for Treating Diseases Related to Mch Receptor

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990005723A1 (fr) * 1988-11-24 1990-05-31 Yoshitomi Pharmaceutical Industries, Ltd. Composes de trans-4-amino(alkyl)-1-pyridylcarbamoylcyclohexane et leur utilisation en medecine
WO1997046250A1 (fr) * 1996-06-04 1997-12-11 Synaptic Pharmaceutical Corporation Procedes de modification du comportement alimentaire, composes utiles dans lesdits procedes, et adn codant un recepteur y5 atypique hypothalamique de neuropeptide y/peptide yy
EP1430033A4 (fr) * 2001-08-31 2004-12-15 Univ Northwestern Composition anti-inflammatoire et inhibitrice de la proteine kinase et methode d'utilisation

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5989920A (en) * 1994-12-02 1999-11-23 Synaptic Pharmaceutical Corporation Methods of modifying feeding behavior compounds useful in such methods and DNA encoding a hypothalmic atypical neuropeptide Y/peptide YY receptor Y5
US20030125269A1 (en) * 1998-08-26 2003-07-03 Ming Li T-type calcium channel
US20070037836A1 (en) * 2001-10-01 2007-02-15 Yoshinori Sekiguchi Mch receptor antagonists
US20060025397A1 (en) * 2001-10-26 2006-02-02 Hee-Sup Shin Method of resistance of epilepsy by suppressing the function of alpha 1g protein
US20030086980A1 (en) * 2001-11-02 2003-05-08 Hee-Sup Shin Method for the suppression of visceral pain by regulating T type calcium channel
US20030087799A1 (en) * 2001-11-07 2003-05-08 Jakob Wolfart Modulation
US20060003985A1 (en) * 2002-10-17 2006-01-05 Renger John J Enhancement of sleep with t-type calcium channel antagonists
US20040197825A1 (en) * 2003-01-15 2004-10-07 Millennium Pharmaceuticals, Inc. Methods and compositions for treating urological disorders using 44390, 54181, 211, 5687, 884, 1405, 636, 4421, 5410, 30905, 2045, 16405, 18560, 2047, 33751, 52872, 14063, 20739, 32544, 43239, 44373, 51164, 53010, 16852, 1587, 2207, 22245, 2387, 52908, 69112, 14990, 18547, 115, 579, 15985, 15625, 760, 18603, 2395, 2554, 8675, 32720, 4809, 14303, 16816, 17827, 32620, 577, 619, 1423, 2158, 8263, 15402, 16209, 16386, 21165, 30911, 41897, 1643, 2543, 9626, 13231, 32409, 84260, 2882, 8203, 32678, or 55053
US20070010671A1 (en) * 2003-03-31 2007-01-11 Yoshinori Sekiguchi Novel quinazoline derivatives and methods of treatment related to the use thereof
US20070129347A1 (en) * 2004-05-10 2007-06-07 Gruenenthal Gmbh Cyclohexylacetic acid compounds
US20080090863A1 (en) * 2004-09-30 2008-04-17 Taisho Pharmaceutical Co., Ltd. Pyridine Derivatives and Their Use as Medicaments for Treating Diseases Related to Mch Receptor

Cited By (22)

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Publication number Priority date Publication date Assignee Title
US8362021B2 (en) 2006-05-11 2013-01-29 Zalicus Pharmaceuticals Ltd. Method for increasing the bioavailability of benzhydryl piperazine containing compounds
US20090312346A1 (en) * 2006-05-11 2009-12-17 Neuromed Pharmaceuticals Ltd. Method for increasing the bioavailability of benzhydryl piperazine containing compounds
US9096522B2 (en) 2008-06-02 2015-08-04 Zalicus Pharmaceuticals, Ltd. N-piperidinyl acetamide derivatives as calcium channel blockers
US8377968B2 (en) 2008-06-02 2013-02-19 Zalicus Pharmaceuticals, Ltd. N-piperidinyl acetamide derivatives as calcium channel blockers
US8569344B2 (en) 2008-06-02 2013-10-29 Zalicus Pharmaceuticals Ltd. N-piperidinyl acetamide derivatives as calcium channel blockers
US20090298883A1 (en) * 2008-06-02 2009-12-03 Hassan Pajouhesh N-piperidinyl acetamide derivatives as calcium channel blockers
US8273900B2 (en) * 2008-08-07 2012-09-25 Novartis Ag Organic compounds
US20100035898A1 (en) * 2008-08-07 2010-02-11 David Beattie Organic compounds
US20120220564A1 (en) * 2009-09-18 2012-08-30 Zalicus Pharmaceuticals Ltd. Selective calcium channel modulators
US8409560B2 (en) 2011-03-08 2013-04-02 Zalicus Pharmaceuticals Ltd. Solid dispersion formulations and methods of use thereof
US8591944B2 (en) 2011-03-08 2013-11-26 Zalicus Pharmaceuticals Ltd. Solid dispersion formulations and methods of use thereof
US9340549B2 (en) 2012-03-05 2016-05-17 Amgen Inc. Oxazolidinone compounds and derivatives thereof
US10208023B2 (en) 2013-03-01 2019-02-19 Mark G. DeGiacomo Heterocyclic inhibitors of the sodium channel
JP2017538678A (ja) * 2014-11-05 2017-12-28 フレクサス・バイオサイエンシーズ・インコーポレイテッドＦｌｅｘｕｓ Ｂｉｏｓｃｉｅｎｃｅｓ， Ｉｎｃ． 免疫調節剤
EP3215141A4 (fr) * 2014-11-05 2018-06-06 Flexus Biosciences, Inc. Agents immunorégulateurs
US10106546B2 (en) 2014-11-05 2018-10-23 Flexus Biosciences, Inc. Immunoregulatory agents
US10533014B2 (en) 2014-11-05 2020-01-14 Flexus Biosciences, Inc. Immunoregulatory agents
US11242319B2 (en) 2014-11-05 2022-02-08 Flexus Biosciences, Inc. Immunoregulatory agents
US11932601B2 (en) 2014-11-05 2024-03-19 Flexus Biosciences, Inc. Immunoregulatory agents
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US11649207B2 (en) 2019-07-11 2023-05-16 Praxis Precision Medicines, Inc. Formulations of T-type calcium channel modulators and methods of use thereof
US12077502B2 (en) 2019-07-11 2024-09-03 Praxis Precision Medicines, Inc. Formulations of T-type calcium channel modulators and methods of use thereof

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